1. Field
The present invention relates to novel nitrile derivatives, their manufacture and use as medicaments. In particular, the invention relates to novel nitrile derivatives of formula (I)
2. Description
Cysteine proteases have been viewed as lysosomal mediators of terminal protein degradation. Several newly discovered members of this enzyme class, however, are regulated proteases with limited tissue expression, which implies specific roles in cellular physiology and thus would allow a specific targeting of these activities without interfering with the general lysosomal protein degragation. Development of inhibitors of specific cysteine proteases promises to provide new drugs for modifying immunity, osteoporosis, neurodegeneration, chronic inflammation, cancer and malaria (Brxc3x6mme, Drug News Perspect 1999, 12(2), 73-82; Chapman et al., Annu. Rev. Phys. 1997, 59, 63-88).
Cysteine proteases can be grouped into two superfamilies: the family of enzymes related to interleukin 1xcex2 converting enzyme (ICE), and the papain superfamily of cysteine proteases. Presently there are at least 12 human proteases of the papain family from which sequences have been obtained (cathepsin B, L, H, S, O, K, C, W, F, V(L2), Z(X) and bleomycin hydrolase). Cathepsin K was first discovered as a cDNA prominent in rabbit osteoclasts and referred to as OC-2 (Tezuka et al., J. Biol. Chem. 1994, 269, 1106-1109). Recent observations indicate that cathepsin K is a very potent mammalian elastase. Cathepsin K, as well as cathepsins S and L, are also potent collagenases and gelatinases. Macrophages appear capable of mobilizing the active proteases within endosomal and/or lysosomal compartments to the cell surface under special circumstances. In this case, the cell surface/substrate interface becomes a compartment from which endogenous inhibitors are excluded and can be viewed as a physiological extension of the lysosome. This type of physiology is an innate trait of osteoclasts, a bone macrophage, and may also be exploited by other macrophages or cells in the context of inflammation. The abundance of cathepsin K in osteoclasts suggests that cathepsin K plays an important role in bone resorption. Studies revealed that cathepsin K is the predominant cysteine protease in osteoclasts and is specifically expressed in human osteoclasts. A correlation between inhibition of cysteine protease activity and bone resorption has been reported (Lerner et al., J. Bone Min. Res. 1992, 7, 433; Everts et al., J. Cell. Physiol. 1992, 150, 221). Cathepsin K has been detected in synovial fibroblasts of RA patients, as well as in mouse hypertrophic chondrocytes (Hummel et al., J. Rheumatol. 1998, 25(10), 1887-1894.). Both results indicate a direct role of cathepsin K in cartilage erosion. P. Libby (Libby et al., J. Clin. Invest. 1998, 102 (3), 576-583) reported that normal arteries contain little or no cathepsin K or S whereas macrophages in atheroma contained abundant immunoreactive cathepsins K and S. Most of the elastolytic activity of tissue extracts associated with human atheroma compared to non-atherosclerotic arteries could be inhibited with E64, a non-selective cysteine protease inhibitor.
Tumor progression and metastasis are characterized by the invasion of tumors into adjacent tissues as well as by the dissociation of cancer cells from primary tumors and the infiltration of metastatic cells into organs. These processes are associated with the degragation of extracellular matrix proteins and thus require proteolytic activity. Cathepsin K has been identified in primary breast tumors, as well as in breast tumor-derived bone metastasis (Littlewood-Evans et al., Cancer Res. 1997, 57, 5386-5390).
Different classes of compounds, such as aldehydes, xcex1-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts, epoxy succinyl compounds, vinyl sulfones, aminoketones, and hydrazides have been identified as cysteine protease inhibitors (Schirmeister et al., Chem. Rev. 1997, 97, 133-171; Veber et al., Proc. Natl. Acad. Sci. USA 1997, 94, 14249-14254). The shortcomings these compounds suffer from include lack of selectivity, poor solubility, rapid plasma clearance and cytotoxicity. A need therefore exists for novel inhibitors useful in treating diseases caused by pathological levels of proteases, such as cysteine proteases, including cathepsins, and especially cathepsin K. Therefore, a need exists for compounds that are selective inhibitors of cathepsin K.
The subject invention provides compounds of the formula: 
wherein
Y is O, S, or CHxe2x80x94R2;
R1 and R3 are each independently hydrogen or methyl and R2 is hydrogen, or R1 is hydrogen and R2 and R3 together are xe2x80x94CH2xe2x80x94 thus forming a cyclopropyl ring;
R4, R5 are each independently hydrogen or lower-alkyl;
R6 is cycloalkyl, aryl, aryl-lower-alkyl, heteroaryl, or heteroaryl-lower-alkyl;
R7 is xe2x80x94COxe2x80x94Ra, xe2x80x94SO2xe2x80x94Rb or xe2x80x94CSxe2x80x94NHxe2x80x94Rc, wherein
Ra is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, aryl, heteroaryl, aryl-lower-alkyl, aryl-lower-alkoxy, heteroaryl-lower-alkoxy, aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl, arylthio-lower-alkyl, aryl-lower-alkenyl, aryl-cycloalkyl, or Rdxe2x80x94NH,
Rb is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, or aryl-lower-alkenyl,
Rc is lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, or heteroaryl-lower-alkyl,
Rd is aryl-lower-alkyl;
or a pharmaceutically acceptable salt or ester thereof.
A preferred group of compounds are of the formula: 
wherein Y, R1, R3, R4, R5, R6 and R7 are as defined above.
Another favored group of compounds are of the formula: 
wherein
R6xe2x80x2 is aryl;
R7xe2x80x2 is xe2x80x94COxe2x80x94Raxe2x80x2 or xe2x80x94CSxe2x80x94NHxe2x80x94Rcxe2x80x2, wherein
Raxe2x80x2 is cycloalkyl-lower-alkyl, aryl-lower-alkyl, aryl-lower-alkoxy, aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl, and
Rcxe2x80x2 is heteroaryl-lower-alkyl;
or a pharmaceutically acceptable salt or ester thereof.
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The present invention also relates to processes for the preparation of the compounds of formula (I). 
wherein
Y represents O, S, or CHxe2x80x94R2,
R1 and R3 independently from each other represent hydrogen or methyl and R2 represents hydrogen, or R1 represents hydrogen and R2 and R3 together are xe2x80x94CH2xe2x80x94 to form a cyclopropyl ring,
R4, R5 independently from each other represent hydrogen or lower-alkyl,
R6 represents cycloalkyl, aryl, aryl-lower-alkyl, heteroaryl, or heteroaryl-lower-alkyl,
R7 represents xe2x80x94COxe2x80x94Ra, xe2x80x94SO2xe2x80x94Rb or xe2x80x94CSxe2x80x94NHxe2x80x94Rc, wherein
Ra represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, aryl, heteroaryl, aryl-lower-alkyl, aryl-lower-alkoxy, heteroaryl-lower-alkoxy, aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl, arylthio-lower-alkyl, aryl-lower-alkenyl, aryl-cycloalkyl, or Rdxe2x80x94NH,
Rb represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, or aryl-lower-alkenyl,
Rc represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, or heteroaryl-lower-alkyl,
Rd represents aryl-lower-alkyl,
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
The nitriles derivatives of the present invention have an inhibitory activity on cysteine proteases, more paticulary on cysteine proteases of the papain superfamily, even more paticularly on cysteine proteases of the cathepsin family, most particularly on cathepsin K. It was surprisingly found, that this inhibiting effect on cathepsin K is selective with respect to other cathepsins. While compounds of formula (I) very efficiently inhibit cathepsin K, the inhibition of other protease inhibitors such as cathepsin S, cathepsin L and cathepsin B is much weaker. Therefore the new compounds of formula (I) are usefull for specifically inhibiting cathepsin K. They can accordingly be used for the treatment of disorders which are associated with cysteine proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease. Accordingly, the present invention relates to a method for the prophylactic and/or therapeutic treatment of diseases which are associated with cystein proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease, which method comprises administering a compound of formula (I) to a human being or an animal. The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant. Furthermore, the present invention relates to the use of such compounds for the preparation of medicaments for the treatment of disorders which are associated with cystein proteases.
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term xe2x80x9clowerxe2x80x9d is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term xe2x80x9calkylxe2x80x9d refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms.
The term xe2x80x9clower-alkylxe2x80x9d refers to a branched or straight chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a monovalent carbocyclic radical of 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms.
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred and chlorine and bromine being more preferred.
The term xe2x80x9calkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is an alkyl. The term xe2x80x9clower-alkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is a lower-alkyl.
The term xe2x80x9carylxe2x80x9d relates to the phenyl or naphthyl group which can optionally be mono- or multiply-substituted by alkyl, halogen, hydroxy, alkoxy, xe2x80x94Oxe2x80x94(CH2)1-7xe2x80x94Oxe2x80x94, aryloxy, or arylalkoxy. Substitution in meta- or in meta- and para-position is preferred. Preferred substituents are lower-alkyl, fluorine, chlorine, bromine, lower-alkoxy, methylenedioxy, and aryl-lower-alkoxy. More preferred substituents are chlorine, bromine, methoxy, and benzyloxy. Another preferred substituted phenyl group is the benzo[1,3]dioxol-5-yl group.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic 5- or 6-membered ring which can contain 1 or 2 atoms selected from nitrogen, oxygen or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, with furyl and thienyl being preferred. The term xe2x80x9cheteroarylxe2x80x9d further refers to bicyclic heteroaromatic ring systems such as e.g. indolyl. A heteroaryl group may have a substitution pattern as described earlier in connection with the term xe2x80x9carylxe2x80x9d.
An aryl-lower-alkyl group may optionally comprise a second aryl group, e.g. a phenyl group, at the lower-alkyl moiety.
The term xe2x80x9caryloxyxe2x80x9d relates to a group aryl-Oxe2x80x94. The term xe2x80x9carylthioxe2x80x9d relates to a group aryl-Sxe2x80x94.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
The term xe2x80x9cpharmaceutically acceptable estersxe2x80x9d embraces esters of the compounds of formula (1), in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
In detail, the present invention refers to compounds of formula (I) 
wherein
Y represents O, S, or CHxe2x80x94R2,
R1 and R3 independently from each other represent hydrogen or methyl and R2 represents hydrogen, or
R1 represents hydrogen and R2 and R3 together are xe2x80x94CH2xe2x80x94 to form a cyclopropyl ring,
R4, R5 independently from each other represent hydrogen or lower-alkyl,
R6 represents cycloalkyl, aryl, aryl-lower-alkyl, heteroaryl, or heteroaryl-lower-alkyl,
R7 represents xe2x80x94COxe2x80x94Ra, xe2x80x94SO2xe2x80x94Rb or xe2x80x94CSxe2x80x94NHxe2x80x94Rc, wherein
Ra represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, aryl, heteroaryl, aryl-lower-alkyl, aryl-lower-alkoxy, heteroaryl-lower-alkoxy, aryl-lower-alkoxy-lower-alkyl, aryloxy-lower-alkyl, arylthio-lower-alkyl, aryl-lower-alkenyl, aryl-cycloalkyl, or Rdxe2x80x94NH,
Rb represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, or aryl-lower-alkenyl,
Rc represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, or heteroaryl-lower-alkyl,
Rd represents aryl-lower-alkyl,
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
In a preferred embodiment, the present invention relates to compounds as described above, wherein
R7 represents xe2x80x94COxe2x80x94Ra, xe2x80x94SO2xe2x80x94Rb or xe2x80x94CSxe2x80x94NHxe2x80x94Rc, wherein
Ra represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, cycloalkyl-lower-alkoxy, aryl, heteroaryl, aryl-lower-alkyl, aryl-lower-alkoxy, heteroaryl-lower-alkoxy, aryl-lower-alkoxy-lower-alkyl, or Rdxe2x80x94NH,
Rb represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, or aryl-lower-alkenyl,
Rc represents lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl, heteroaryl, aryl-lower-alkyl, or heteroaryl-lower-alkyl,
Rd represents aryl-lower-alkyl,
and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
The compounds of formula (I) have at least 2 asymmetric carbon atoms and can exist in the form of optically pure enantiomers or as racemates. The invention embraces all of these forms. Preferred compounds of formula (I) are compounds of formula (Ia) which are derived from the corresponding S-proline derivatives. 
wherein Y, R1, R3, R4, R5, R6 and R7 are as defined above, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof.
Compounds of formula (I) in which Y represents CHxe2x80x94R2 are preferred, with those wherein R2 is hydrogen being particularly preferred. Compounds of formula (I) in which R1, R3, R4 and/or R5 represent hydrogen are also preferred. Another preferred embodiement refers to compounds of formula (I) in which R6 is phenyl, furanyl, thiophenyl, or pyrrolyl, optionally substituted with alkyl, halogen, hydroxy, alkoxy, xe2x80x94Oxe2x80x94(CH2)1-7xe2x80x94Oxe2x80x94, aryloxy, or aryl-alkoxy. Further, compounds of formula (I) in which R6 represents phenyl, phenyl substituted in meta-position, phenyl substituted in meta- and in para-position or benzo[1,3]dioxol-5-yl are also preferred with 3-methoxy-phenyl, 3,4-dimethoxy-phenyl, 4-benzyloxy-3-methoxy-phenyl, 3-chloro-phenyl, 3-bromo-phenyl, or benzo[1,3]dioxol-5-yl being especially preferred.
Compounds of formula (I) in which R7 represents xe2x80x94COxe2x80x94Ra and Ra is as defined above are preferred. Compounds of formula (I) in which R7 represents xe2x80x94COxe2x80x94Ra and Ra is benzyloxy, cyclopentyl-ethylene, or benzyloxy-methylene are especially preferred. Further, compounds of formula (I) in which R7 represents xe2x80x94COxe2x80x94Ra and Ra is 3-bromobenzyl, 4-bromobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, or 2-methyl-phenyloxymethylene are also especially preferred. A further preferred embodiement are compounds of formula (I) in which R7 represents xe2x80x94CSxe2x80x94NHxe2x80x94Rc and Rc is as defined above. Compounds of formula (I) in which R7 represents xe2x80x94CSxe2x80x94NHxe2x80x94Rc and Rc is benzyl, 3-fluorobenzyl, or furan-2-yl-methylene are especially preferred. Another preferred embodiement relates to compounds of formula (I), wherein R7 represents xe2x80x94SO2xe2x80x94Rb and Rb is as defined above, with those in which Rb is naphthyl being particularly preferred.
Preferred compounds of formula 1 are
(1RS,2RS,5SR)-2-{[(RS)- or -[(SR)-Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester,
(S)-2-[(R)-(Cyano-phenyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-[(S)-(Cyano-phenyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-1-(3-methyl-butyryl)-pyrrolidine-2-carboxylic acid (R)- and (S)-(cyano-phenyl-methyl)-amide,
(S)-2-{(S)- and (R)-[Cyano-(3-methoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-{(S)- and (R)-[Cyano-(3-hydroxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-[(R)- and (S)-(Cyano-cyclopropyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-[(R)- and (S)-(Benzo[1,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acidbenzyl ester,
(R)-4-{(R)- and (S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-thiazolidine-3-carboxylic acid benzyl ester,
(2S,3R)-2-{(R)- and (S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-3-methyl-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-1-Benzylthiocarbamoyl-pyrrolidine-2-carboxylic acid ((R)- and (S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide,
(S)-1-Benzylthiocarbamoyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[(Furan-2-ylmethyl)-thiocarbamoyl]-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-Benzylthiocarbamoyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]-amide,
(S)-1-(3-Fluoro-benzylthiocarbamoyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]-amide,
(S)-2-((R)- and (S)-1-Cyano-3-phenyl-propylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester,
(R)-4-{(R)- and (S)-[(4-Chloro-phenyl)-cyano-methyl]-carbamoyl}-thiazolidine-3-carboxylic acid benzyl ester,
(S)-2-{(R)- and (S)-[(3-Chloro-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-[(R)- and (S)-(Cyano-o-tolyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-{(R)- and (S)-[Cyano-(2,4-dimethoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-{(R)- and (S)-[(3-Bromo-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-{(R)- and (S)-[Cyano-(3-fluoro-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-[(R)- and (S)-(Cyano-m-tolyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-{(R)- and (S)-[(4-Bromo-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-{(R)- and (S)-[Cyano-(3,4,5-trimethoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-{(R)- and (S)-[Cyano-(3-phenoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-{(R)- and (S)-[(4-Benzyloxy-3-methoxy-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-1-(Naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(Naphthalene-1-sulfonyl)-pyrrolidine-2-carboxylic acid ((R)- and (S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide,
(S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid ((R)- and (S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide,
(S)-1-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid ((R)- and (S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide,
(S)-1-(5-Dimethylamino-naphthalene-1-sulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and
(S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(Naphthalene-1-sulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(Naphthalene-2-carbonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(Naphthalene-1-carbonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(Naphthalene-1-carbonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]-amide,
(S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]-amide,
(S)-1-Phenylacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]-amide,
(S)-1-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]-amide,
(S)-Pyrrolidine-1,2-dicarboxylic acid 2-{[(R)- and (S)-(3-chloro-phenyl)-cyano-methyl]-amide}1-[(R)-(1-naphthalen-1-yl-ethyl)-amide],
(S)-1-(Naphthalene-1-carbonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-bromo-phenyl)-cyano-methyl]-amide,
(S)-1-Phenylacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-bromo-phenyl)-cyano-methyl]-amide,
(S)-1-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-(3-bromo-phenyl)-cyano-methyl]-amide,
(S)-Pyrrolidine-1,2-dicarboxylic acid 2-{[(R)- and (S)-(3-bromo-phenyl)-cyano-methyl]-amide}1-[(R)-(1-naphthalen-1-yl-ethyl)-amide],
(S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3-methoxy-phenyl)-methyl]-amide,
(S)-1-Phenylacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3-methoxy-phenyl)-methyl]-amide,
(S)-1-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3-methoxy-phenyl)-methyl]-amide,
2-((R)- and (S)-1-Cyano-3-phenyl-propylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-{(R)- and (S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-1-(2-Phenyl-ethenesulfonyl)-pyrrolidine-2-carboxylic acid ((R)- and (S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide,
(S)-Pyrrolidine-1,2-dicarboxylic acid 2-{(R)- and (S)-[cyano-(3,4-dimethoxy-phenyl)-methyl]-amide}1-[(S)-(1-naphthalen-1-yl-ethyl)-amide],
(S)-1-(2-Phenyl-ethenesulfonyl)-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide,
and pharmaceutically acceptable esters thereof.
Other preferred compounds of formula 1 are
(S)-1-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-[2-(4-Iodo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(4-Phenyl-butanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(2-Benzo[1,3]dioxol-5-yl-ethanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(2-Phenoxy-ethanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(2-Benzo[1,3]dioxol-5-yl-ethanoyl)-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-(2-Phenoxy-ethanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(2-Phenyl-ethanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-[2-(4-Fluoro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(2-Benzo[1,3]dioxol-5-yl-ethanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(3-Phenyl-propanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[4-(3,4-Dimethoxy-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[4-(3,4-Dimethoxy-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-[2-(4-Iodo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[4-(3,4-Dimethoxy-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(3-1H-Indol-3-yl-propanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(4-Phenyl-butanoyl)-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-(2-Phenylsulfanyl-ethanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(4-Cyclohexyl-butanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(3-Cyclohexyl-propanoyl)-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[4-(4-Nitro-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(4-Iodo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl)-amide,
(S)-1-[2-(2,4-Dimethyl-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-[4-(4-Nitro-phenyl)-butanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(1-Naphthalen-1-yl-methanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-[2-(4-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(2-Phenyl-ethanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(2-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(4-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(4-Cyclohexyl-butanoyl)-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-{1-[1-(4-Chloro-phenyl)-cyclopentyl]-methanoyl}-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-((Z)-3-Phenyl-allanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(2-Phenylsulfanyl-ethanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(4-Fluoro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-[2-(3-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(4-Phenyl-butanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-[2-(3,4,5-Trimethoxy-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(5-Phenyl-pentanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-(1-Cyclopropyl-methanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(4-Fluoro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[2-(4-Chloro-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(2-Phenyl-ethanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(3,3-Diphenyl-propanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(3-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[2-(4-Ethoxy-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-(5-Phenyl-pentanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(5-Phenyl-pentanoyl)-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[2-(2,4-Dimethyl-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[2-(2-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-(3-Cyclohexyl-propanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-[2-(3-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-[3-(2,3,4-Trimethoxy-phenyl)-propanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(2-Benzyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(1-Cyclopropyl-methanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-[2-(2-Methoxy-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro -phenyl)-1-cyano-methyl]-amide,
(S)-1-(1-Cyclohexyl-methanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(4-Ethoxy-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[3-(3,4,5-Trimethoxy-phenyl)-propanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(Naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3-phenoxy-phenyl)-methyl]-amide,
(S)-1-(Naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-(3-Cyclopentyl-propanoyl)-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-(3-Cyclopentyl-propanoyl)-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-(3-Fluoro-benzylthiocarbamoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide, and
(S)-1-[2-(2,4-Dimethyl-phenoxy)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide.
Especially preferred compounds of formula (I) are
(S)-2-[(R)-(Cyano-phenyl-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester,
(2S,3R)-2-{(R)- and (S)-[Cyano-(3,4-dimethoxy-phenyl)-methyl]-carbamoyl}-3-methyl-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-[(R)- and (S)-(Benzo[1,3]dioxol-5-yl-cyano-methyl)-carbamoyl]-pyrrolidine-1-carboxylic acidbenzyl ester,
(S)-2-{(R)- and (S)-[(3-Bromo-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-2-{(R)- and (S)-[(3-Chloro-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester,
(S)-1-Benzyloxyacetyl-pyrrolidine-2-carboxylic acid ((R)- and (S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide,
(S)-1-(3-Cyclopentyl-propionyl)-pyrrolidine-2-carboxylic acid ((R)- and (S)-benzo[1,3]dioxol-5-yl-cyano-methyl)-amide,
(S)-2-{(R)- and (S)-[(4-Benzyloxy-3-methoxy-phenyl)-cyano-methyl]-carbamoyl}-pyrrolidine-1-carboxylic acid benzyl ester, and
(S)-1-[(Furan-2-ylmethyl)-thiocarbamoyl]-pyrrolidine-2-carboxylic acid [(R)- and (S)-cyano-(3,4-dimethoxy-phenyl)-methyl]-amide.
Other especially preferred compounds of formula (I) are
(S)-1-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[2-(3-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-(3-chloro-phenyl)-1-cyano-methyl]-amide,
(S)-1-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide,
(S)-1-[2-(4-Chloro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide,
(S)-1-[2-(4-Fluoro-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide, and
(S)-1-[2-(4-Bromo-phenyl)-ethanoyl]-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
Other especially preferred compounds of formula (I) are
(S)-1-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid [1-cyano-1-(3,4-dimethoxy-phenyl)-methyl]-amide, and
(S)-1-(2-o-Tolyloxy-ethanoyl)-pyrrolidine-2-carboxylic acid (1-benzo[1,3]dioxol-5-yl-1-cyano-methyl)-amide.
The invention also relates to compounds of formula (IV) 
wherein Y, R1, R3, R4, R5 and R6 have the same significances as given for compounds of formula (I).
The invention also relates to the use of compounds as defined above for the treatment or prophylaxis of diseases which are associated with cysteine proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease. In a preferred embodiement, the invention relates to the use of compounds as defined above for the treatment or prophylaxis of osteoporosis, instable angina pectoris or plaque rupture.
Further, the invention relates to compounds as defined above for use as therapeutic active substances, in particular in context with diseases which are associated with cysteine proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease. In a preferred embodiement, the invention relates to compounds as defined above for use as therapeutic active substances in context with osteoporosis, instable angina pectoris or plaque rupture.
The invention also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant, in particular for use in context with diseases which are associated with cysteine proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease. In a preferred embodiement, the invention relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant for use in context with osteoporosis, instable angina pectoris or plaque rupture.
A further embodiment of the present invention refers to the use of compounds as defined above for the preparation of medicaments for the treatment or prophylaxis of diseases which are associated with cystein proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease. In a preferred embodiement, the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment or prophylaxis of osteoporosis, instable angina pectoris or plaque rupture. Such medicaments comprise a compound as defined above.
An additional embodiment of the invention relates to a method for the prophylactic and/or therapeutic treatment of disorders in which cathepsin K plays a significant pathological role, such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease, which method comprises administering a compound as defined above to a human being or an animal. A preferred embodiement of the invention relates to a method for the prophylactic and/or therapeutic treatment of osteoporosis, instable angina pectoris or plaque rupture, which method comprises administering a compound as defined above to a human being or an animal.
The invention further relates to a process for the manufacture of compounds of formula (I) which process comprises
a) reacting a compound of formula (II) 
with a compound of formula (III) 
wherein Y, R1, R3, R5, R6 and R7 have the significances given above, or
b) reacting a compound of formula (IV) 
with a compound of formula (V), (VI), (VII) or (VIII) 
wherein Y, R1, R3, R4, R5, R6, Ra, Rb, Rc and Rd have the significances given above.
The invention also relates to a process as described above, which process comprises the preparation of pharmaceutically acceptable salts and/or pharmaceutically acceptable esters. The formation of the esters and/or salts can be carried out at different stages of the process, e.g. with the compound of formula (I) or with the corresponding starting materials.
The reaction of a compound of formula (II) with a compound of formula (III) can be carried out by methods known to the person skilled in the art. The reaction can conveniently be carried out by dissolving compound (II), compound (III), TPTU (O-1,2-Dihydro-2-oxo-1-pyridyl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate) and Hxc3xcnigsbase (N-Ethyldiisopropylamine) in MeCN and stirring the mixture at room temperature for 6 to 16 hours. The reaction mixture can be concentrated and the product can be obtained by methods known to the person skilled in the art, e.g. by extraction and column chromatography. Alternatively, a compound of formula (II) can be dissolved in CH2Cl2 and reacted for 6 to 16 hours at room temperature with a compound of formula (III) in the presence of N-methylmorpholin, HOBT and EDCI. The product can be obtained by, methods known per se, e.g. by extraction and HPLC.
The reaction of a compound of formula (IV) with a compound of formula (V), (VI), (VII) or (VIII) is conveniently carried out by preparing a solution of compound (IV) in CH2Cl2 and adding a solution of compound (V), (VI) or (VII) in CH2Cl2. To this mixture, Triethylamin is added and after shaking 6 to 16 hours at room temperature formic acid is added. The product can be isolated and purified by methods known per se, e.g. by evaporation of the solvent and HPLC.
In order to prepare pharmaceutically acceptable salts and/or pharmaceutically acceptable esters of compounds of formula (I), it is possible to prepare the corresponding esters and/or salts starting from the compounds of formula (I). It is also possible, to form the esters and/or salts at an earlier stage, e.g. to form the corresponding salts an/or esters of the corresponding starting materials. The methods to prepare pharmaceutically acceptable salts and/or pharmaceutically acceptable esters as defined before are known in the art.
Compounds of formula (II) are prepared by methods already known to the person skilled in the art. Conveniently, the corresponding amino acid is converted to the corresponding methyl ester by reacting the amino acid in MeOH in the presence of thionylchloride. The resulting intermediate product is isolated by methods known per se, e.g. by extraction and evaporation of the solvent. The intermediate product is linked to the desired substituent R7 analogously to the method described above. The methyl ester is then saponified to yield a compound of formula (II) by dissolving the methyl ester and 2 N NaOH in MeOH and stirring the mixture 5 to 16 hours at room temperature. The resulting compound (II) is isolated by methods known per se, e.g. by extraction and evaporation of the solvent.
Compounds of formula (III) can conveniently be obtained by adding a solution of the corresponding aldehyde in CH2Cl2 to a solution of NH4Cl and NaCN in H2O and MeOH at 0xc2x0 C. The mixture is stirred and allowed to warm to room temperature. After addition of NH3 solution and completion of the reaction the resulting compound of formula (III) is isolated and purified by methods known to the person skilled in the art, e.g. by extraction. The corresponding hydrochlorid can be prepared by methods known per se.
Chiral compounds of formula (III) can conveniently be obtained by adding ammonia to a mixed anhydride (prepared from a suitable t-BOC protected amino acid and isobutylchloroformate) at xe2x88x9210xc2x0 C. The reaction mixture is stirred at room temperature for 1-5 h. After completion of the reaction the resulting t-BOC protected amino acid amide is isolated and purified by methods known to the person skilled in the art, e.g. by extraction. The Boc protected amino acid amide and triethylamine are dissolved in THF and trifluoroacetic acid anhydride at 0xc2x0 C. The mixture is stirred for 1-5 h at 0xc2x0 C., then at room temperature for 1-2 h. After isolation and purification of the resulting intermediate product, e.g. by evaporation of the solvent and flash chromatography, the t-BOC protective group can be cleaved off with HCl in acetic acid to yield the desired compound of formula (III).
Compounds of formula (IV) can conveniently be obtained by reacting the corresponding t-BOC protected amino acid with a compound of formula (III) analogous to the method described above. After isolation and purification of the resulting intermediate product, e.g. by evaporation of the solvent and flash chromatography, the t-BOC protective group can be cleaved off with trifluoro-acetic acid to yield the desired compound of formula (IV) with trifluoro-acetic acid.
Compounds of formula (V), (VI), (VII) and (VIII) are either commercially available or can be obtained by methods known in the art.
The present invention relates to all compounds of formula (I), as prepared by one of the processes described above.
The inhibitory activity of the compounds against cathepsin K, S, L and B was tested at room temperature in 96-wells opaque white polystyrene plates (Costar). The cathepsin K inhibitory activity was tested as follows:
5 xcexcl of an inhibitor diluted in 5 mM sodium phosphate, NaCl 15 mM pH 7.4 containing 1% DMSO (final concentrations: 10xe2x88x920.0001 xcexcM) were preincubated for 10 min with 35 xcexcl of human recombinant cathepsin K (final concentration: 1 nM) diluted in assay buffer (100 mM sodium acetate pH 5.5 containing 5 mM EDTA and 20 mM cysteine). After addition of 10 xcexcl of the fluorogenic substrate Z-Leu-Arg-MCA diluted in assay buffer (final concentration: 5 xcexcM), increase of fluorescence (excitation at 390 nm and emission at 460 nm) was measured for 7.5 min every 45 sec. The initial velocity (RFU/min) was derived from the linear fit of the 11 reading points.
The cathepsin B inhibitory activity was assayed under the same conditions as the cathepsin K inhibitory activity using human liver cathepsin B (Calbiochem) at a final concentration of 1 nM.
The cathepsin L inhibitory activity was assayed under the same conditions as the cathepsin K inhibitory activity using human liver cathepsin L (Calbiochem) at a final concentration of 3 nM.
Cathepsin S inhibitory activity was assayed analogeously to the cathepsin K inhibitory activity, except that the buffer was 100 mM potassium phosphate, 5 mM EDTA, 5 mM DTT (freshly added), 0.01% Triton X-100, pH 6.5 and the fluorogenic substrate was Z-Val-Val-Arg-MCA (Bachem) (final concentration: 20 xcexcM). Human recombinant cathepsin S (Wiederanders et al., Eur. J. Biochem. 1997, 250, 745-750) was used at a final concentration of 0.5 nM.
The results are given as IC50 values which denote the concentration of the inhibitor at which the enzymatic activity is inhibited by 50%. The IC50 values are determined from a linear regression curve from a logit-log plot.
It will be appreciated that the compounds of formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo.
As mentioned earlier, medicaments containing a compound of formula (I) are also an object of the present invention, as is a process for the manufacture of such medicaments, which process comprises bringing one or more compounds of formula (I) and, if desired, one or more other therapeutically valuable substances into a galenical administration form.
The pharmaceutical compositions may be administered orally, for example in the form of tablets, coated tablets, dragxc3xa9es, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be carried out rectally, for example using suppositories; locally or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally, using for example injectable solutions. Furthermore, administration can be carried out sublingually or as opthalmological preparations or as an aerosol, for example in the form of a spray.
For the preparation of tablets, coated tablets, dragxc3xa9es or hard gelatine capsules the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients for tablets, dragxc3xa9es or hard gelatine capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof.
Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid or liquid polyols etc.; according to the nature of the active ingredients it may however be the case that no excipient is needed at all for soft gelatine capsules.
For the preparation of solutions and syrups, excipients which may be used include for example water, polyols, saccharose, invert sugar and glucose.
For injectable solutions, excipients which may be used include for example water, alcohols, polyols, glycerine, and vegetable oils.
For suppositories, and local or percutaneous application, excipients which may be used include for example natural or hardened oils, waxes, fats and semi-solid or liquid polyols.
The pharmaceutical compositions may also contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the variation of osmotic pressure, buffers, coating agents or antioxidants. As mentioned earlier, they may also contain other therapeutically valuable agents.
It is a prerequisite that all adjuvants used in the manufacture of the preparations are non-toxic.
Intravenous, intramuscular or oral administration is a preferred form of use. The dosages in which the compounds of formula (I) are administered in effective amounts depend on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of application. In general, daily dosages of about 1 mg-1000 mg, preferably 5 mg-500 mg, per day come into consideration.